Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/103—Measuring devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
  • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb
  • A61B5/1124—Determining motor skills
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
  • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
  • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q2600/00—Oligonucleotides characterized by their use
  • C12Q2600/156—Polymorphic or mutational markers

Definitions

• Primary mitochondrial disease comprises a heterogeneous group of genetic conditions that impair the ability to generate cellular energy.
• Kremer et al. Mitochondrial Disease Genetics in Diagnosis and Management of Mitochondrial Disorders; Mancuso and Klopstock (Eds); Springer 2019; pp 41-62 .
• the disease affects at least 1 in 4,300 individuals with a highly variable, but often progressive array of multi-systemic manifestations.
• Gorman et al. Ann. Neurol. 2015; 77:753-9 .
• the more severe manifestations can lead to significant morbidity and mortality.
• Two studies of affected children found mortality rates of 35% and 36%, respectively, during their childhood years. Scaglia et al., Pediatrics.
• Mitochondrial disease typically impacts multiple organs. For example, gastrointestinal (GI) involvement and nutritional deficit are common. GI involvement has been reported in 29% ( Debray et al., Pediatrics. 2007; 119(4):722-33 ) to 48% ( Skladal et al., Clin. Pediatr. 2003; 42(8):703-10 ) of pediatric patients with mitochondrial disease. Major GI symptoms can include persistent vomiting, failure to thrive, and dysphagia. Swallowing difficulties frequently inhibit sufficient oral food intake and may result in aspiration or chest infection. Kisler et al., Dev. Med. Child. Neurol. 2010; 52(5):422-33 . 48% of adult patients with mitochondrial disease experience problems with swallowing. Read et al., Int. J. Lan. Commun. Disord. 2012; 47:106-11 .
• Enteral tube feeding is indicated in some patients with such neurologic symptoms. Braegger et al., J Pediatr. Gastroenterol. Nutr. 2010 Jul; 51(1):110-22 . Nasogastric tube feeding is feasible for up to several months, and gastrostomy is the appropriate option if feeding problems persist. Research shows that gastrostomy benefits pediatric patients with neurodevelopmental diseases in terms of clinical progress and quality of life. Kisler et al., Dev. Med. Child. Neurol. 2010; 52(5):422-33 . In one study of pediatric mitochondrial disease patients, the majority of patients had GI symptoms requiring enteral tube feeding, with oropharyngeal dysphagia being the most common indication, apparent in 81% of patients. Choi and Lee, Scientific Reports 2017; 7: 16909 .
• the disclosed liquid formulation of probucol will have significant medical utility and will increase the number of patients with mitochondrial disease who can be treated with probucol, by administration through nasogastric, gastrostomy or jejunostomy tubes. Furthermore, the liquid formulation of probucol enables the more accurate and convenient dosing of probucol to pediatric patients including neonates, who present a wide range of body weights that present challenges for both dose calculation and methods of administration.
• ophthalmoplegia and ptosis as in Chronic Progressive External Ophthalmoplegia (CPEO), including Kearns-Sayre Syndrome (KSS); Gronlund et al., Br. J. Ophthalmol.
• CPEO Chronic Progressive External Ophthalmoplegia
• KSS Kearns-Sayre Syndrome
• GSS Kearns-Sayre Syndrome
• CPEO a complex disorder that impairs extraocular muscle mobility in association with ptosis, is the most common ocular manifestation of mitochondrial myopathies; Schoser and Pongratz, Strabismus. 2006; 14(2):107-13 .
• LHON is characterized by acute and painless central vision loss of both eyes in a sequential fashion over a period of days to months.
• Certain ophthalmologic diseases that have not traditionally been considered to have obvious mitochondrial origins are increasingly recognized to result in part from impaired mitochondrial function, increased oxidative stress, and increased apoptosis.
• Schrier and Falk Curr. Opin. Ophthalmol. 2011; 22(5): 325-331 .
• the eye is particularly susceptible to the consequences of mitochondrial damage.
• Jarrett et al. Ophthalmic Res. 2010; 44(3):179-90 .
• Ophthalmic disorders that involve mitochondrial dysfunction include diabetic retinopathy and Age-related Macular Degeneration (AMD). Mohammad et al., Lab. Invest. 2010;90(9):1365-1372 ).
• Kenney et al. Invest. Ophthalmol. Vis. Sci. 2010; 51(8):4289-4297 .
• Local topical administration of probucol for ophthalmic conditions provides certain advantages over systemic administration. Eye drops can result in greater delivered local dosages directly to the eye, and can alleviate the challenges of systemic administration with regard to the transport of probucol across the blood-brain barrier.
• Probucol is relatively water-insoluble and is known to be absorbed preferentially by high fat tissue, a property that can enhance uptake by clinically relevant components of the eye.
• Probucol is relatively insoluble in water. Hendler et al. described water-soluble phosphate esters of probucol, in order to generate different types of formulations. International Application No. WO9924400 . The claims address using this water-soluble formulation to treat oxidative damage. Oxidative stress is caused by many physiologic conditions, including certain mitochondrial diseases, but this work does not describe the use of water-soluble phosphate esters of probucol to treat any underlying mitochondrial disease.
• Yoshitaka proposed a novel antidiabetic treatment and prophylactic medicine which contains probucol or a salt or solvate thereof.
• Japanese Patent Application No. JP2000319441A This invention addresses the use of probucol to prevent diabetes by protecting pancreatic beta-cells from oxidative stress. While some patients with mitochondrial diseases experience diabetes, this condition is only one of numerous manifestations of mitochondrial dysfunction. In this work, probucol was proposed to target pancreatic beta-cells alone, and thus is not proposed as a multi-organ or broad spectrum therapeutic agent. Probucol is presented as a preventative agent against diabetes and not as a treatment for underlying mitochondrial disease or other symptoms thereof.
• a macromolecular structure was described that comprised two branched peptide chains capable of forming water-soluble micelles to deliver therapeutic agents to mitochondria.
• compositions and methods have been described for increasing the cellular respiration of melanized catecholamine neurons, and methods were described for alleviating symptoms or stopping appearance and/or progression of symptoms of Parkinson's disease and related conditions, characterized by nigrostriatal degeneration.
• U.S. Patent Application No. 20020198231 is described for increasing the cellular respiration of melanized catecholamine neurons, and methods were described for alleviating symptoms or stopping appearance and/or progression of symptoms of Parkinson's disease and related conditions, characterized by nigrostriatal degeneration.
• Probucol been described as one of many potential antioxidants to be used in conjunction with mitochondrial activators, including pyrroloquinoline quinone and coenzyme Q, for the prophylaxis or treatment of disease caused by mitochondrial dysfunction.
• mitochondrial activators including pyrroloquinoline quinone and coenzyme Q
• the invention relates to a method of treating a human subject with a disease caused by mitochondrial dysfunction comprising administering an amount of probucol effective to maintain or improve mitochondrial function.
• the diagnosis of said mitochondrial dysfunction is based in whole or part on the presence of at least one mutation or variant in the subject's DNA.
• the invention also relates to a method of treating a human subject with a disease caused by mitochondrial dysfunction comprising: (a) obtaining a biological sample from the human subject, (b) detecting the presence in DNA from said sample of at least one mutation or variant associated with mitochondrial dysfunction, and (c) administering to the human subject with said DNA mutation or variant associated with mitochondrial dysfunction probucol or a pharmaceutically acceptable salt thereof in an amount effective to maintain or improve mitochondrial function.
• the human subject has a mitochondrial disease selected from the group consisting of: autosomal dominant optic atrophy (ADOA); beta-oxidation defects; carnitine deficiency; carnitine-acyl-carnitine deficiency; chronic progressive external ophthalmoplegia syndrome (CPEO); co-enzyme Q10 deficiency; complex I deficiency (NADH dehydrogenase deficiency); complex II deficiency (succinate dehydrogenase deficiency); complex III deficiency (ubiquinone-cytochrome c oxidoreductase deficiency); complex IV deficiency (cytochrome c oxidase deficiency or COX deficiency'); complex V deficiency (ATP synthase deficiency); multiple respiratory chain complex deficiency; carnitine palmitoyltransferase (CPT) I deficiency; CPT II deficiency; diabetes mellitus
• the at least one mutation or variant is in a mitochondrial DNA encoded gene selected from the group consisting of MT-ATP6, MT-ATP8, MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MT-RNR1, MT-RNR2, MT-TA, MT-TC, MT-TE, MT-TF, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TQ, MT-TS1, MT-TS2, MT-TV and MT-TW.
• MT-ATP6, MT-ATP8, MT-CO1, MT-CO2, MT-CO3, MT-CYB MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND
• the at least one mutation or variant is in a nuclear DNA encoded gene selected from the group consisting of AARS2, ABCC8, ACAD9, ACADM, ACADS, ACADVL, ACAT1, ACO2, ADCK3, ADRB2, ADRB3, AFG3L2, AGK, AGRP, AIFM1, AK2, AKT2, ALDH2, AMT, APOPT1, ATP5A1, ATP5E, ATP5F1A, ATP5F1D, ATP5F1E, ATPAF2, AUH, BCS1L, BOLA3, C10orf2, C12orf65, C19orf12, C1QBP, CAPN10, CARS2, CARTPT, CDH23, CDKAL1, CHCHD10, CHKB, CISD2, CLRN1, COA5, COA7, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ9, COX10, COX14, COX15, COX20, COX6B1, COX8A, C
• the at least one mutation or variant is in a nuclear DNA encoded gene selected from the group consisting of ABCB7, ACADSB, AKAP10, ALAS2, ALDH4A1, ALDH6A1, AMACR, APTX, ARMS2, BAX, BCAT2, BCKDHA, BCKDHB, BCL2, C12orf62, C20orf7, C8orf38, COX4I2, CRAT, CYB5R3, CYCS, CYP11A1, CYP11B1, CYP11B2, CYP24A1, CYP27A1, CYP27B1, D2HGDH, DBT, DECR1, DHODH, DIABLO, DLD, DMGDH, FH, GDAP1, GK, GLRX5, GLUD1, HCCS, HIBCH, HK1, HLCS, HMGCL, HOGA1, HTRA2, IDH3B, IVD, KARS, KIF1B, L2HGDH, LRRK2, MA
• the disease is liver failure and the DNA mutation or variant is in the TFAM gene.
• the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges was explicitly recited.
• the range of "1 mg to about 10,000 mg” is inclusive of the endpoints, 1 mg and 10,000 mg, and all the intermediate values.
• a range of numerical values is stated herein as being greater than a stated value, the range is nevertheless finite and is bounded on its upper end by a value that is operable within the context of the invention as described herein.
• the disclosure is directed to methods of treating or preventing mitochondrial dysfunction or mitochondrial disease in a subject, comprising administering to the subject probucol, or a pharmaceutically acceptable salt thereof, wherein the administration results in an improvement or delayed onset of one or more clinical symptoms selected from fatigue, muscle weakness, neuromuscular dysfunction, exercise intolerance, balance problems, dysautonomia, gastrointestinal problems, vision problems, eye muscle problems, retinal problems, optic nerve problems, ptosis, headache, dehydration, peripheral neuropathy, numbness, epilepsy, seizures, sleep problems, mood disorder, depression, diabetes mellitus, weight problems, kidney dysfunction, hyperlipidemia, liver disease, sleep apnea, autism spectrum behavior, behavioral problems, delayed developmental milestones, heart rhythm problems, heart muscle problems, cardiac disease, stroke, speech problems, tinnitus, hearing impairment, intellectual disability, learning disability, cognitive impairment, dementia, or a combination thereof.
• one or more clinical symptoms selected from fatigue, muscle weakness, neuromuscular dysfunction, exercise intolerance, balance problems, dysautonomia,
• the improvement or delayed onset of one or more clinical symptoms is clinically significant.
• clinically significant it is meant to include one or more improvements that one of ordinary skill in the art would consider (i) statistically significant, or (ii) practically important in that it has an observable positive effect on daily life.
• clinically significant improvements can be improvements of pre-selected symptoms, as compared to pre-defined severity thresholds.
• a clinically significant improvement of select symptoms includes the absence of statistically significant deterioration in any of other symptoms.
• a clinically significant improvement includes an improvement in a quality of life parameter.
• classifying the subject as a member of a clinical category may mean classifying the subject as having a normal or abnormal measurement.
• classifying the subject as a member of a metric range may mean classifying the subject as falling within or outside a pre-defined numeric range.
• said two or more measurement instruments are selected from Six Minute Walk Test, Motor Function Measure, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale and Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales.
• said two or more measurement instruments are the Six Minute Walk Test, Motor Function Measure, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale and Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales.
• Most of these measurement instruments, including how to conduct, measure, and evaluate them, are known in the art. Karaa et al., J. Inherit. Metab. Dis. 2017; 40(3):403-14 .
• the measurement instrument is a Motor Function Measure. In another aspect, the measurement instrument is a Six Minute Walk Test. In a further aspect, the measurement instrument is a Two Minute Walk Test. In one aspect, the measurement instrument is a Modified Fatigue Impact Scale. In another aspect, the measurement instrument is a Friedreich's Ataxia Rating Scale. In a further aspect, the measurement instrument is a Patient-Reported Outcomes Measurement Information System Gastrointestinal Scale(s). In one aspect, the measurement instrument is a 30-Second Chair Stand Test. In another aspect, the measurement instrument is a Muscle Strength by Myometry Test. In another aspect, the measurement instrument is a Newcastle Mitochondrial Disease Adult Scale.
• the measurement instrument is a Newcastle Mitochondrial Disease Pediatric Scale. In one aspect, the measurement instrument is a 36-Item Short Form Survey. In another aspect, the measurement instrument is a Clinical Global Impression. In another aspect, the measurement instrument is a Patient's Global Impression. In another aspect, the measurement instrument is a Patient-Reported Initial MitoPC Symptoms. In a further aspect, the measurement instrument is a Patient-Reported MitoPC Symptom Changes. In a further aspect, the measurement instrument is a Columbia Suicide Severity Rating Scale. In one aspect, the measurement instrument is a Neuropathy Impairment Score. In another aspect, the measurement instrument is a Migraine Disability Assessment.
• the measurement instrument is a Quick Inventory of Depressive Symptomatology - Self-Report. In one aspect, the measurement instrument is a Montreal Cognitive Assessment. In another aspect, the measurement instrument is a NY Heart Association Functional Classification. In a further aspect, the measurement instrument is a Diabetes Health Profile. In one aspect, the measurement instrument is an Ocular Motility Assessment(s). In another aspect, the measurement instrument is a Marginal Reflex Distance. In a further aspect, the measurement instrument is an Ocular Motility & Fixation in 8 Gaze Directions. In one aspect, the measurement instrument is a Degree of Ocular Saccades. In another aspect, the measurement instrument is a Visual Function Test. In another aspect, the measurement instrument is a Logarithm of Minimum Angle of Resolution.
• the methods disclosed herein further comprise administering one or more additional pharmaceutical agents.
• pharmaceutical agents means approved or approvable by a regulatory agency of the United States Federal or a state government, or a corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and, more particularly, in humans.
• the subject is diagnosed as having a genetic mitochondrial disease prior to the administration.
• the diagnosis of mitochondrial disease my involve cellular or tissue biopsy-based biochemical investigations or massively parallel DNA or RNA sequencing in blood and/or tissue.
• the nucleic acid is DNA.
• the nucleic acid is RNA.
• the nature, abundance and location of chemical modifications to component nucleotides in the nucleic acid are employed for diagnostic purposes.
• the method of the present disclosure may comprise selecting and/or isolating a genetic mutation or variation of interest, and quantifying the amount of each locus present (for example for determining copy number) and/or the relative amounts of different locus variants (for example two alleles of a given DNA sequence).
• a genetic mutation or variation may have a reference sequence associated with it.
• "Reference sequence” as used herein denotes a sequence to which a locus of interest in a nucleic acid is being compared. In certain embodiments, a reference sequence is considered a "wild type" sequence for a locus of interest.
• a nucleic acid that contains a locus of interest having a sequence that varies from a reference sequence for the locus of interest is sometimes referred to as polymorphic or mutant or genetic variation.
• a nucleic acid that contains a locus of interest having a sequence that does not vary from a reference sequence for the locus of interest is sometimes referred to as wild type or non-genetic variation.
• a locus of interest may have more than one distinct reference sequence associated with it (e.g., where a locus of interest is known to have a polymorphism that is to be considered a normal or wild type).
• the region of interest described herein may include "consensus genetic variant sequence” which refers to the nucleic acid or protein sequence, the nucleic or amino acids of which are known to occur with high frequency in a population of individuals who carry the gene which codes for a mitochondrial dysfunction.
• the region of interest described herein may include "consensus normal gene sequence” which refers to a nucleic acid sequence, the nucleic acid of which is known to occur at the respective positions with high frequency in a population of individuals who carry the gene which codes for a protein not functioning normally, or which itself does not function normally.
• control region that is not the region of interest or the reference sequence described herein may include "consensus normal sequence" which refers to the nucleic acid or protein sequence, the nucleic or amino acids of which are known to occur with high frequency in a population of individuals who carry the gene which codes for a normally functioning protein, or in which the nucleic acid itself has normal function.
• the at least one pathologic nucleic acid mutation is a nuclear DNA (nDNA) mutation or a combination of nDNA mutations.
• nDNA-encoded genes associated with mitochondrial disease when mutated include, but are not limited to, AARS2, ABCB7, ABCC8, ACAD8, ACAD9, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ACO2, ADCK3, ADRB2, ADRB3, AFG3L2, AGK, AGRP, AIFM1, AK2, AKAP10, AKT2, ALAS2, ALDH2, ALDH4A1, ALDH6A1, AMACR, AMT, APOPT1, APTX, ARMS2, ATP5A1, ATP5E, ATP5F1A, APT5F1D, ATP5F1E, ATPAF2, AUH, BAX, BCAT2, BCKDHA, BCKDHB, BCL2, BCS1L, BOLA3, C8orf38, C10orf2, C12orf
• the nucleic acid mutation or variation is in a gene selected from any of the genes recited in Tables 8 or 9 or any combination thereof.
• Table 8 is a classification of genes associated with mitochondrial diseases based on information from from Kremer et al., Mitochondrial Disease Genetics in Diagnosis and Management of Mitochondrial Disorders; Mancuso and Klopstock (Eds); Springer 2019; pp 41-62 .
• Table 9 is based on informaiton from the Mitochondrial Disease Sequence Data Resource (MSeqDR.org). Shen et al., MSeqDR: a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in mitochondrial disease, Hum. Mutat.
• the method may detect from 1 to 100, from 1 to 50, from 1 to 25, from 2 to 10, or from 5 to 10 nucleic acid mutations or variations; 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleic acid mutations or variations; and 100, 50, 30, 20, 10 or less nucleic acid mutations or variations from any of Tables 8 or 9.
• the method according to some embodiments may detect at least two nucleic acid mutations or variations from Tables 8 or 9.
• the method according to some embodiments may detect at least three nucleic acid mutations or variations from Tables 8 or 9.
• the method may according to some embodiments detect at least four nucleic acid mutations or variations from Tables 8 or 9.
• the method according to some embodiments may detect at least five nucleic acid mutations or variations from Tables 8 or 9. In another aspect, the method according to some embodiments may detect at least six nucleic acid mutations or variations from Tables 8 or 9. In another aspect, the method according to some embodiments may detect at least seven nucleic acid mutations or variations from Tables 8 or 9. In another aspect, the method according to some embodiments may detect at least eight nucleic acid mutations or variations from Tables 8 or 9. In another aspect, the method according to some embodiments may detect at least nine nucleic acid mutations or variations from Tables 8 or 9. In another aspect, the method according to some embodiments may detect at least ten nucleic acid mutations or variations from Tables 8 or 9.
• the pathologic nucleic acid mutation is a combination of at least one mtDNA mutation and at least one nDNA mutation, and/or are dependent on mtDNA haplogroup background and/or environmental exposure.
• the mitochondrial dysfunction is associated with neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Huntington's disease.
• the mitochondrial dysfunction is associated with cognition, psychiatric, and/or mood impairment.
• the mitochondrial dysfunction is associated with Alzheimer's disease.
• the mitochondrial dysfunction is associated with cardiac dysfunction.
• the subject is a geriatric adult, for example, the subject is 65 years or older or 70 years or older.
• the geriatric subject can be 65 years or older, 66 years or older, 67 years or older, 68 years or older, 69 years or older, 70 years or older, 71 years or older, 72 years or older, 73 years or older, 74 years or older, 75 years or older, or 80 years or older.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 10,000 mg. In other embodiments, probucol, or pharmaceutically acceptable salts thereof, is administered at a dose of about 1 mg to about 5,000 mg. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg/day to about 1,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg to about 500 mg. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg to about 100 mg.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 500 mg. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg to about 1,000 mg. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 10,000 mg. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 5,000 mg. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 1,000 mg.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 1,000 mg to about 5,000 mg. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5,000 mg to about 10,000 mg.
• probucol, or a pharmaceutically acceptable salt thereof may be administered at a dosing interval of twice per day, twice per week, twice per month, three times per day, three times per week, three times per month, four times per day, four times per week or four times per month, without intermission.
• probucol, or a pharmaceutically acceptable salt thereof is administered twice per day, once per day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks or once per month.
• once weekly dosing means that probucol, or a pharmaceutically acceptable salt thereof, is administered once a week, i.e. one time during a seven day period, preferably on the same day of each week.
• a non-limiting example of administration of a dose of 1,000 mg administered at a dosing interval of once per week would entail administered a single unit dose of 1,000 mg every Sunday.
• the unit dose is not administered on the same or consecutive days, but a dose of twice per week can include a dosing regimen in which unit doses are administered on the same or consecutive days within a weekly period or different weekly periods.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg/day to about 100 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg/day to about 50 mg/day. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg/day to about 10,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg/day to about 5,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg/day to about 1,000 mg/day.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg/day to about 500 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg/day to about 1,000 mg/day. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg/day to about 10,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg/day to about 5,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg/day to about 1,000 mg/day.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg/day to about 500 mg/day. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg/day to about 10,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg/day to about 5,000 mg/day. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg/day to about 1,000 mg/day. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1,000 mg/day to about 10,000 mg/day.
• probucol, or a pharmaceutically acceptable salt thereof is administered at a dose of about 1,000 mg/day to about 5,000 mg/day. In aspects of the disclosure, probucol, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5,000 mg/day to about 10,000 mg/day.
• probucol, or a pharmaceutically acceptable salt thereof is administered on an intermittent dosing schedule.
• intermittent dosing schedule refers to non-continuous drug administration at a prescribed frequency (e.g. daily) with intermission.
• probucol, or a pharmaceutically acceptable salt thereof may be administered daily for four weeks, followed by two weeks off, followed again by daily administration for four weeks.
• probucol, or a pharmaceutically acceptable salt thereof is administered initially in a loading dose that is higher than a subsequent dose. In other embodiments, probucol, or a pharmaceutically acceptable salt thereof, is administered initially in a loading dose that is lower than a subsequent dose.
• probucol or a pharmaceutically acceptable salt thereof, is administered in combination with food.
• the food is a high fat food.
• high fat foods include oils, meat, whole-milk dairy, butter, eggs, nuts, seeds, and avocados.
• AE treatment related adverse event
• CCAE Common Terminology Criteria for Adverse Events
• an AE is any untoward medical occurrence in a subject who has received an intervention (drug, biologic, or other intervention). The occurrence does not necessarily have to have a causal relationship with the study treatment.
• An AE can therefore be any unfavorable or unintended incident (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
• Grade numbers refers to the severity of the AE, where grade 1 is least severe and grade 5 is death related to AE.
• the methods disclosed herein may not result in a grade 4 or grade 5 adverse event.
• the treatments described herein may result in no more than a grade 1 adverse event.
• the treatments described herein may result in no more than a grade 2 adverse event.
• the treatments described herein may result in no more than a grade 3 adverse event.
• the disclosure is further directed to methods of diagnosing mitochondrial dysfunction or genetic mitochondrial disease in a subject, comprising (a) sequencing the subject's nucleic acid or a portion thereof; (b) comparing the subject's nucleic acid sequence or a portion thereof to one or more sequences in a database comprising reference population and pathologic nucleic acid mutations; and (c) determining whether the subject's nucleic acid sequence has at least one pathologic mutation in the database.
• the pathologic mutation is predicted.
• the pathologic mutation is confirmed.
• aspects of the methods of diagnosis disclosed herein may further comprise administering to the subject from, for example, about 1 mg to about 10,000 mg of probucol, or a pharmaceutically acceptable salt thereof, or any intermediate dose, as described herein, using any of the dosing protocols described herein.
• the administration results in an improvement of fatigue. In certain embodiments, the administration results in an improvement of muscle weakness. In certain embodiments, the administration results in an improvement of neuromuscular dysfunction. In certain embodiments, the administration results in an improvement of exercise intolerance. In certain embodiments, the administration results in an improvement of a balance problem. In certain embodiments, the administration results in an improvement of dysautonomia. In certain embodiments, the administration results in an improvement of a gastrointestinal problem. In certain embodiments, the administration results in an improvement of a vision problem. In certain embodiments, the administration results in an improvement of an eye muscle problem. In certain embodiments, the administration results in an improvement of a retinal problem. In certain embodiments, the administration results in an improvement of an optic nerve problem.
• the administration results in an improvement of ptosis. In certain embodiments, the administration results in an improvement of headache. In certain embodiments, the administration results in an improvement of dehydration. In certain embodiments, the administration results in an improvement of peripheral neuropathy. In certain embodiments, the administration results in an improvement of numbness. In certain embodiments, the administration results in an improvement of epilepsy. In certain embodiments, the administration results in an improvement of seizures. In certain embodiments, the administration results in an improvement of a sleep problem. In certain embodiments, the administration results in an improvement of a mood disorder. In certain embodiments, the administration results in an improvement of a psychiatric disorder. In certain embodiments, the administration results in an improvement of depression.
• the administration results in an improvement of diabetes mellitus. In certain embodiments, the administration results in an improvement of a weight problem. In certain embodiments, the administration results in an improvement of kidney dysfunction. In certain embodiments, the administration results in an improvement of hyperlipidemia. In certain embodiments, the administration results in an improvement of liver disease. In certain embodiments, the administration results in an improvement of sleep apnea. In certain embodiments, the administration results in an improvement of autism spectrum behavior. In certain embodiments, the administration results in an improvement of a behavioral problem. In certain embodiments, the administration results in an improvement of a delayed developmental milestone. In certain embodiments, the administration results in an improvement of a heart rhythm problem. In certain embodiments, the administration results in an improvement of a heart muscle problem.
• the administration results in an improvement of cardiac disease. In certain embodiments, the administration results in an improvement of stroke. In certain embodiments, the administration results in an improvement of a speech problem. In certain embodiments, the administration results in an improvement of tinnitus. In certain embodiments, the administration results in an improvement of a hearing impairment. In certain embodiments, the administration results in an improvement of an intellectual disability. In certain embodiments, the administration results in an improvement of a learning disability. In certain embodiments, the administration results in an improvement of a cognitive impairment. In certain embodiments, the administration results in an improvement of dementia.
• said two or more measurement sub-instruments are validated outcome measures for mitochondrial dysfunction or mitochondrial disease.
• Example 1 A Phase II Randomized, Double-Blind, Placebo-Controlled, Two-Period Crossover Study to Assess the Safety and Efficacy of Probucol in Adults with Genetically-Confirmed Mitochondrial Disease
• the primary objectives of this study are to evaluate, among other things, (i) the efficacy of probucol, or pharmaceutically acceptable salts thereof, as compared to placebo, by measuring the proportion of subjects that are responders over a 16-week treatment period when assessed by the Mitochondrial Disease Personalized Composite (MitoPC) endpoint, which is based on the most prevalent symptoms in patients with mitochondrial disease, and (ii) the safety of probucol, or pharmaceutically acceptable salts thereof, using adverse event (AE) rates, laboratory values, and electrocardiogram results.
• the selection of symptoms for inclusion in the MitoPC endpoint were based on a survey of mitochondrial disease symptoms in adult and pediatric mitochondrial disease patients. Zolkipli-Cunningham et al., PLoS One 2018; 13(5):e0197513 .
• the key secondary objective of this study is to evaluate the efficacy of probucol, or pharmaceutically acceptable salts thereof, as compared to placebo over a 16-week treatment period as measured by the Six Minute Walk Test (6MWT).
• Other secondary objectives include evaluating the efficacy of probucol, or pharmaceutically acceptable salts thereof, compared to placebo over a 16-week treatment period. The following evaluations will be conducted for all subjects:
• Exploratory objectives of this study include evaluating the safety and efficacy of probucol, or pharmaceutically acceptable salts thereof, compared to placebo over a 16-week treatment period as measured by:
• Active participation will last for approximately 15 months and will include up to 13 on-site visits to the clinical study center. If there are sudden safety concerns, additional on-site visits may be required.
• Subjects who meet the eligibility criteria will be screened at Visit 1 and complete the pre-treatment phase. Subjects will complete a standardized intake of their active clinical symptoms. The investigator will discuss the disease manifestations of each subject so that they have a full understanding of the severity of their disease and relevance of their specific symptoms. Each subject will then: (1) identify the presence or absence of five specific symptoms on the MitoPC menu by completing the five MitoPC sub-instruments for all five specific symptoms, regardless of whether or not such symptoms are present; (2) indicate whether or not each symptom has a personal impact and whether or not the subject seeks its improvement (by completing the PRIMS assessment); and (3) rank the symptoms in order of importance to the subject and degree of negative impact on their life (by completing the PRIMS assessment).
• 6MWT threshold is determined by gender, age, height and weight. 6
• the stated MCID is for the Six Minute Walk Test. 7
• the subject meets the OMA threshold in V1 if s/he meets or exceeds any of the sub-assessent thresholds (one or more of MRD1, OMF8, DOS). 8
• the subject meets the VFT threshold in V1 if s/he meets or exceeds any of the sub-assessent thresholds (one or more of LogMAR, PRS, VFMD).
• Visit V1 must be no more than 8 weeks before Visit V2.
• Each subject will be monitored for QTc prolongation during their entire participation and, if needed, they will be safely removed from the study if prolongation of QTc is more than 60 msec compared to baseline or an absolute QTc greater than 500 msec. Re-challenge with the study drug may be considered only if the QTc interval returns to within 10 msec of baseline and absolute QTc of less than or equal to 450 msec.
• subjects will be closely monitored for any cardiovascular conditions or abnormalities, and if required, removed from the study and referred to a cardiologist for consult.
• SAE serious adverse event
• CCAE Common Terminology Criteria for Adverse Events
• Subjects who complete the double-blind treatment phase will proceed with the post-treatment phase, which includes a minimum of two safety evaluations on-site and/or by telephone.
• MitoPC MitoPC symptoms assessed and sub-instruments Symptom Sub-Instrument Code Exercise intolerance 6-Minute Walk Test 6MWT Muscle weakness Motor Function Measure (32 items) MFM-32 Fatigue Modified Fatigue Impact Scale MFIS Balance problems Friedreich's Ataxia Rating Scale FARS Gastrointestinal Patient-Reported Outcomes Measurement Information PROMIS-GI symptoms System - Gastrointestinal Symptom Scales
• a "Sub-instrument Responder” is defined as subject who achieves an improvement from treatment period baseline that equals or exceeds the MCID for that sub-instrument (i.e., an assessment of "Better").
• a “MitoPC Responder” is a subject who is a "Sub-instrument Responder” for at least one of the up to five “qualified sub-instruments” in that subject's personalized MitoPC, in the absence of a clinically meaningful deterioration in any of the other "qualified sub-instruments” (Table 5).
• MitoPC Responder Definitions MitoPC Sub-Instruments # Symptom Sub-Instrument Assessment Definition 1 Exercise intolerance Six-Minute Walk Test Better 6MWT Responder Neutral or Worse 6MWT Non-Responder 2 Muscle weakness Motor Function Measure Better MFM-32 Responder Neutral or Worse MFM-32 Non-Responder 3 Fatigue Modified Fatigue Impact Scale Better MFIS Responder Neutral or Worse MFIS Non-Responder 4 Balance problems Friedreich's Ataxia Rating Scale Better FARS Responder Neutral or Worse FARS Non-Responder 5 GI problems Patient-Reported Outcomes Measurement Information System - Gastrointestinal Symptoms Better PROMIS-GI Responder Neutral or Worse PROMIS-GI Non-Responder MitoPC Responder Responder on any of the "qualified sub-instruments", with no assessment of Worse for any of the "qualified sub-instruments" MitoPC Non-Responder Non-Responder on all of
• the primary efficacy endpoint will be evaluated by comparing the proportion of "MitoPC Responders" in the drug and placebo treatment arms for each 16-week treatment period of the crossover study.
• MitoPC Sub-Instrument Threshold Values are defined as the score that corresponds to a "mild" disease or symptom severity rating in literature, or the clinical equivalent thereof. These values were determined by a literature review and evaluation by a committee of mitochondrial disease clinicians and experts.
• Brennan et al. Am. J. Gastroenterol. 2014; 109:1804-1814 . Flachenecker et al., Multiple Sclerosis 2002; 8:523-526 .
• Subramony et al. Neurology 2005; 64:1261-1262 .
• Berard et al. Neuromuscular Disorders 2005; 15:463-470 . Enright and Scherrill, Am. J. Respir. Crit. Care Med. 1998; 158:1384-1387 .
• the key secondary endpoint for this study is the change in the 6MWT score from treatment period baseline.
• the other secondary endpoints are the changes from treatment period baseline in the following endpoints:
• exploratory objectives to evaluate the safety and efficacy of probucol, or pharmaceutically acceptable salts thereof, compared to placebo over a 16-week treatment period are included, as measured by the exploratory objectives listed above.
• the McNemar's test will be used to test the null hypothesis of whether the probability of a subject being a "MitoPC Responder” after treatment with probucol, or pharmaceutically acceptable salts thereof, is the same as the probability of being a "MitoPC Responder” after treatment with placebo. Specifically, the McNemar's exact binomial test will be used for these calculations, since the expected number of discordant pairs may be relatively small ( ⁇ 25).
• Analysis Populations All analyses will be performed for at least one of the following analysis populations. Details will be described in the SAP.
• treatment period baseline For the evaluation of the 6MWT, change from treatment period baseline will be calculated at 16 weeks. Probucol, or pharmaceutically acceptable salts thereof, will be compared to placebo using a linear mixed model including terms for sequence, treatment, and period as fixed effects and subjects nested within sequence as a random effect. Treatment period baseline 6MWT score will also be included in the model, but will be removed if not statistically significant at the 0.05 level. The model will be evaluated for normality and heterogeneity of variance assumptions and nonparametric methods will be considered, if appropriate.
• Descriptive statistics (N, mean, standard deviation, minimum, median, maximum) will be presented for the 6MWT scores and other secondary endpoints at each time-point and for change from treatment period baseline.

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